The long term goal of this project is to understand the structure- function relationships of the common Beta-subunit (CD18) shared by members of the CD11/CD18 leukocyte adhesion glycoprotein family. These glyoproteins, which include the cell surface complexes LFA-1, Mac-1, and p150,95, have recently been identified as members of the integrin supergene family. The CD11/CD18 complexes participate in virtually all aspects of the normal inflammatory response. Each member of the CD11/CD18 family consists of an identical Beta-subunit (CD18) and a distinct Alpha-subunit (CD11a, b, or c). The CD18 molecule contains domains required for interactions with the Alpha-subunit to form Alpha, Beta complexes, glycosylation, and cell-surface receptor interactions. The overall importance of this family of glycoproteins in normal immune defense mechanisms has been emphasized by the recognition of a group of patients with heritable leukocyte adhesion deficiency (LAD). LAD represents the most severe example of generalized prepubescent periodontitis in humans and is one of a limited number of periodontal syndromes for which a molecular basis has been defined. The genetic defects of these patients result in heterogeneous abnormalities of the CD18 subunit and are reflected in the patients' inability to synthesize, process, and express normal CD11/CD18 complexes on myeloid and lymphoid cell surfaces. Clinically, the severity of the infectious morbidity and mortality of these patients is directly related to the extent of the molecular defects in the CD18 molecule. The sequence of the normal CD18 subunit has been determined at the nucleic acid level and the cDNA is available. Together, the cDNA and the patient population provide a unique opportunity to define the structural features of CD18 that are responsible for normal processing and function of the CD11/CD18 complexes and to determine the molecular basis for the abnormalities of adherence- dependent leukocyte inflammatory functions which result in associated periodontal disease. The lesions in the patients' CD18 molecules will be identified at the DNA level using a modification of the polymerase chain reaction (PCR) to amplify the patients' defective CD18 mRNAs and by subsequent sequencing of the PCR products. The functional domains of the CD18 molecule will be localized using the naturally occurring mutant cDNAs and the normal CD18 cDNA modified by in vitro mutagenesis. The new mutant cDNAs will be expressed in an appropriate cultured cell line and the functional significance of the structural changes introduced by these mutations will be examined using immunoprecipitation to detect CD11/CD18 complex formation, endoglycosidase H to monitor glycosylation, flow cytofluorography to measure cell surface expression, and bioassays for intercellular adhesion reactions.